PDF(Pubmed)
Abstract：
The emergence of acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) is almost inevitable even after a remarkable clinical response. Secondary mutations such as T790M and C797S are responsible for the resistance to 1st/2nd-generation (1/2G) TKIs and 3G TKIs, respectively. To overcome both the T790M and C797S mutations, novel 4G EGFR-TKIs are now under early clinical development. In this study, we evaluated the efficacy of a 4G EGFR-TKI in the treatment of lung cancer with EGFR mutation as well as explored resistance mechanisms to a 4G TKI. First, we compared the efficacies of seven TKIs including a 4G TKI, BI4020, against Ba/F3 cell models that simulate resistant tumors after front-line osimertinib treatment failure because of a secondary mutation. We also established acquired resistant cells to BI4020 by chronic drug exposure. Ba/F3 cells with an osimertinib-resistant secondary mutation were refractory to all 3G TKIs tested (alflutinib, lazertinib, rezivertinib, almonertinib, and befotertinib). BI4020 inhibited the growth of C797S-positive cells; however, it was not effective against L718Q-positive cells. Erlotinib was active against all Ba/F3 cells tested. In the analysis of resistance mechanisms of BI4020-resistant (BIR) cells, none harbored secondary EGFR mutations. HCC827BIR cells had MET gene amplification and were sensitive to a combination of capmatinib (MET-TKI) and BI4020. HCC4006BIR and H1975BIR cells exhibited epithelial-to-mesenchymal transition. This study suggests that erlotinib may be more suitable than 4G TKIs to overcome secondary mutations after front-line osimertinib. We found that off-target mechanisms that cause resistance to earlier-generation TKIs will also cause resistance to 4G TKIs.
摘要：
即使在显著的临床反应之后,对EGFR-酪氨酸激酶抑制剂(TKIs)的获得性抗性的出现几乎是不可避免的。次级突变如T790M和C797S负责对第一代/第二代（1/2G）TKI和3GTKI的抗性，分别。为了克服T790M和C797S突变，新型4GEGFR-TKIs目前正在早期临床开发中。在这项研究中,我们评估了4GEGFR-TKI治疗EGFR突变肺癌的疗效,并探讨了4GTKI的耐药机制.首先,我们比较了包括4GTKI在内的七个TKI的功效，BI4020，针对Ba/F3细胞模型，该模型在奥希替尼一线治疗失败后模拟耐药肿瘤，因为二次突变。我们还通过长期药物暴露建立了对BI4020的获得性抗性细胞。具有奥希替尼抗性次级突变的Ba/F3细胞对所有测试的3GTKIs都是难治性的（alflutinib，拉泽替尼,瑞齐韦替尼,阿莫替尼,和贝福替尼)。BI4020抑制C797S阳性细胞的生长；然而，它对L718Q阳性细胞无效.厄洛替尼对所有测试的Ba/F3细胞都有活性。在BI4020耐药（BIR）细胞的耐药机制分析中，没有人携带继发性EGFR突变。HCC827BIR细胞具有MET基因扩增并且对卡马替尼(MET-TKI)和BI4020的组合敏感。HCC4006BIR和H1975BIR细胞表现出上皮-间质转化。这项研究表明，埃罗替尼可能比4GTKIs更适合克服一线奥希替尼后的继发性突变。我们发现，导致对前一代TKI产生抗性的脱靶机制也会导致对4GTKI产生抗性。
